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Shoaib, S.;  Ansari, M.A.;  Kandasamy, G.;  Vasudevan, R.;  Hani, U.;  Chauhan, W.;  Alhumaidi, M.S.;  Altammar, K.A.;  Azmi, S.;  Ahmad, W.; et al. Plant-Based Compounds Against SARS-CoV-2. Encyclopedia. Available online: https://encyclopedia.pub/entry/40705 (accessed on 02 July 2024).
Shoaib S,  Ansari MA,  Kandasamy G,  Vasudevan R,  Hani U,  Chauhan W, et al. Plant-Based Compounds Against SARS-CoV-2. Encyclopedia. Available at: https://encyclopedia.pub/entry/40705. Accessed July 02, 2024.
Shoaib, Shoaib, Mohammad Azam Ansari, Geetha Kandasamy, Rajalakshimi Vasudevan, Umme Hani, Waseem Chauhan, Maryam S. Alhumaidi, Khadijah A. Altammar, Sarfuddin Azmi, Wasim Ahmad, et al. "Plant-Based Compounds Against SARS-CoV-2" Encyclopedia, https://encyclopedia.pub/entry/40705 (accessed July 02, 2024).
Shoaib, S.,  Ansari, M.A.,  Kandasamy, G.,  Vasudevan, R.,  Hani, U.,  Chauhan, W.,  Alhumaidi, M.S.,  Altammar, K.A.,  Azmi, S.,  Ahmad, W.,  Wahab, S., & Islam, N. (2023, February 01). Plant-Based Compounds Against SARS-CoV-2. In Encyclopedia. https://encyclopedia.pub/entry/40705
Shoaib, Shoaib, et al. "Plant-Based Compounds Against SARS-CoV-2." Encyclopedia. Web. 01 February, 2023.
Plant-Based Compounds Against SARS-CoV-2
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This entry is adapted from the peer-reviewed paper 10.3390/molecules28020795

Polyphenols and alkaloids are the most widespread plant-based products with prominent properties including anti-cancer, antioxidant, antimalarial, antiviral, antibacterial, antifungal, anti-diabetic, anti-inflammatory, and anti-dengue effects. Accordingly, these phytochemicals can be promising candidates for discovering effective therapeutic regimens for SARS-CoV-2. 

polyphenols SARS-CoV-2 antiviral

1. Plant Products with Anti-Inflammatory and Antioxidant Potential in Various Diseases

Curcumin has been known for centuries to have anti-inflammatory effects, and extensive studies have shown that curcumin may inhibit inflammation-associated signaling pathways in many pathological conditions [1]. Several studies have shown that IL-6 down-regulation is associated with the therapeutic effects of curcumin [2]. Another study demonstrated that curcumin showed anti-inflammatory effects through the inhibition of tumor necrosis factor (TNF)-α, serumIL-6, and c-reactive protein (CRP) [3]. Another study elucidated the important role of chloroquine and amodiaquine, which earlier had been implicated in the treatment and prevention of malaria and inflammatory disease (Table 1). Both chloroquine and amodiaquine have been shown to inhibit interferon (IFN) production [4]. tumor necrosis factor (TNF)-α, NF-, IL-1, and IL-6 are known key regulators in the pathogenesis of rheumatoid arthritis and other inflammatory diseases, and chloroquine has been shown to inhibit IL-1, IL-6, and TNF- production in human monocytes stimulated with lipopolysaccharide [5]. In contrast, hydroxychloroquine has been shown to inhibit IL-1 and IL-6 production in monocytes while leaving IL-2, IL-4, IFN-, and TNF- production unaffected [6]. In a study, chloroquine and hydroxychloroquine were found to exhibit anti-inflammatory potential against phytohemagglutinin and lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC). They discovered that chloroquine and hydroxychloroquine both inhibited IFN- and TNF-production equally [7]. Epigallocatechin gallate (EGCG) attenuates SARS-CoV-2 infection by blocking the interaction of SARS-CoV-2 spike protein receptor-binding domain to human angiotensin-converting enzyme 2 [8].
Anti-inflammatory potential of ascorbic acid has been accomplished by its outstanding power to inhibit the production of IFN-γ while fucoxanthin decreased TNF-α production in human lymphocytes [9]. Ascorbic acid has also been shown to possess immunomodulatory activity, as it inhibits TNF-α and IL-6 production in lipopolysaccharide (LPS)-induced monocytes [10]. Previous studies also indicated the role of ascorbic acid in mitigating the production of TNF-α and IL-6 in LPS-induced macrophages and community-acquired pneumonia [11]. In a few young healthy males, the level of IL-6 was measured before and after the administration of ascorbic acid, and decreased IL-6 production was reported in endothelin-1-induced males [12]. Emodin, an active component of many plants, has previously been reported to prevent the binding of SARS-CoV to ACE2 receptors through the inhibition of spike glycoprotein [13]. Epigallocatechin-3-gallate (EGCG) is a polyphenol found in green tea, and it has been identified with anti-inflammatory, antioxidant, antiviral, and other health-enhancing properties. In vitro studies revealed that polyphenols inhibited the production of many anti-inflammatory cytokines, including IL-6, TNF-α, and IL-8, by inhibiting the cascade that leads to the activation of ERK1/2 and NF-κB [14]. Another study annotated the possible mechanism of EGCG to inhibit Ang II and CRP expression in macrophages [15]. Chemical structures of some of the bioactive compounds active against SARS-CoV-2 and 3C-like proteinase (3CL pro) are presented in Figure 1.
Molecules 28 00795 g001 550
Figure 1. The figure shows chemical structures of plant-derived compounds active against SARS-CoV-2, which have been documented to exert anti-SARS-CoV-2 activities through targeting various pathogenesis-related proteins of SARS-CoV-2 [16].
Polyphenols such as punicalagin, gallic acid, and ellagic acid are well-known antioxidants and have been demonstrated previously to inhibit LPS-stimulated IL-6 production [17]. The recent evidence has shown that punicalagin, a component of pomegranate attenuated the production of IL-6 and TNF-α in lipopolysaccharide (LPS)-induced macrophages [18]. Triphala compounds chebulagic acid, chebulinic acid and gallic acid were also reported to display anti-TNF-α activity in addition to the decreased expression levels of IL-6, IL-8 and MCP-1 which is mediated by inhibition of p38, ERK and NFκB phosphorylation [19]. The anti-inflammatory and antioxidant effects of the phenolic compound resveratrol have been known for decades. In vitro studies reported that resveratrol inhibited TNF-α, IL-8 and IL-6 along with the reduced expression of MCP-1 in human coronary artery smooth muscle cells through the attenuation of extracellular signal-regulated kinase (ERK) [20]. The effect of resveratrol on inflammation and oxidative stress in COPD rats showed that the serum levels of IL-6 and IL-8 were significantly decreased upon treatment with resveratrol [21]. Moreover, the flavonoid quercetin was demonstrated to possess anti-inflammatory and antioxidant potential. Quercetin has been shown to reduce IL-6, TNF-α, and IL-1 production in the LPS-induced macrophage cell line RAW264.77 [22].
Luteolin, a plant product naturally present in several medicinal plants, has attracted wide attention for its health benefits. It significantly reduced the production of TNF-α-induced MCP-1, intercellular cell adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 through the inhibition of nuclear factor kappa B (NF-κB) signaling [23]. In vivo studies showed that luteolin and curcumin synergistically inhibited protein expression of MCP-1 and VCAM-1 in TNF-α-induced monocytes [24]. Apigenin, a flavonoid found in many plants, possesses various health benefits, and several studies have elucidated its anti-inflammatory and antioxidant properties. Several studies found its anti-inflammatory effects in various diseases, including diabetes, sepsis, cancer, atherosclerosis, and other inflammation-based diseases. A study demonstrated that apigenin potentially reduced the expression of many inflammatory molecules such as TNF-α, IL-6, IL-8, and GM-CSF through modulating the expression of NF-κB [25][26]. Fisetin, a flavone found in many plants, was discovered to inhibit IL-6, TNF-α, MCP-1, and IL-8 production in IL-1β-stimulated human lung epithelial cells by inhibiting NF-κB and ERK1/2 [27]. Rutin, a flavonoid present in several fruits, vegetables and medicinal plants has been reported to alleviate the expression of TNF-α and nitric oxide in LPS-induced macrophages [28]. In vitro studies of 3,4-dihydroxytoluene, a Rutin metabolite, revealed that it inhibited nitric oxide (NO), cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) production, as well as the expression of inflammatory cytokines such as IL-6, TNF-α, and IL-1 in LPS-stimulated macrophages [29].
Kaempferol, a flavonoid present in several plant species, has been shown to mollify the secretion of MCP-1 in LPS-induced macrophages [30]. Kaempferol7-O-β-D-glucoside is a natural flavonol glucoside. In vitro studies show that it has the potential to reduce TNF-α, IL-6, IL-1β, iNOS, and COX-2 expression by inhibiting the NF-κB, AP-1, and JAK-STAT signaling pathways in LPS-induced macrophages [31]. Myricetin, a member of the flavonoid class of polyphenols, exhibits antioxidant potential, and the polyphenolic compound has been investigated for its anti-inflammatory properties. A recent study illustrated that myricetin might be responsible for reducing the production of IL-6, TNF-α, NO, and iNOS by suppressing the NF-κB and STAT-1 activation and Nrf-2 mediated Heme oxygenase-1(HO-1) induction in LPS-treated macrophages [32]. Hesperetin, a naturally occurring flavonoid in a few plant species, has been investigated for various health-improving benefits in addition to its antioxidant property. The polyphenolic compound inhibited IL-1β, IL-6 and TNF-α production by modulating the expression of peroxisome proliferator-activated receptor (PPAR)-γ and NF-κB in the bronchoalveolar lavage fluid of rats with ventilator-induced acute lung injury [33]. Another in vitro study suggested that hesperetin treatment may suppress IL-6, TNF-α and IL-1β production and iNOS and COX-2 expression which might be through the inhibition of NF-κB and activation of nuclear factor erythroid 2–related factor 2 (Nrf-2)/HO-1 pathways [34].
Naringenin, a polyphenolic flavonoid found in many citrus fruits and herbs, has been shown to reduce acute inflammation in macrophages by inhibiting IL-6 and TNF-αsecretion [35]. The other study looked into its anti-inflammatory properties and discovered that naringenin inhibited the production of IL-6, TNF-α, and IL-1β. Additionally, abated neutrophil and mononuclear cell recruitment and abrogated myeloperoxidase (MPO) activity were shown to reduce LPS-stimulated inflammatory pain, which possibly occurred through inhibition of the NF-κB pathway [36]. Isorhamnetin was also found to inhibit IL-6 production through the inhibition of NF-κB and STAT-1 signaling pathways in LPS-stimulated macrophages [37]. Some of the flavonoids including chrysin, galangin, quercetin, kaempferol and myricetin were also reported to inhibit IL-1β expression in LPS- and IFN-γ-treated macrophages [38]. Theaflavin, a tea polyphenol, has been known for its antioxidant and anti-cancer properties, and the plant product was also investigated for its anti-inflammatory effects. Theaflavin inhibited LPS-stimulated expression of IL-6, MCP-1, and ICAM-1 by modulating the expression of NF-κB and MAPK [39]. Genistein, an isoflavone mainly present in soybeans, exerts beneficial effects. The isoflavones inhibited IL-6 and TNF-α through suppressing NF-κB pathway activation in LPS-stimulated macrophages [40]. However, attenuated iNOS-derived NO expression was demonstrated in LPS-stimulated macrophages [41]. Baicalein treatment significantly reduced STAT1, STAT3, JAK1 and JAK2 phosphorylation in LPS-induced macrophages which alleviated the production of IL-6, IL-1β and TNF-α and NO [42]. Ferulic acid modulated LPS-induced macrophages expression of anti-inflammatory cytokines such as TNF-α, IL-6 and IL-10 by targeting NF-κB and Nrf-2 pathways [43]. Table 1 shows the anti-inflammatory effects of various phytochemicals.
Table 1. This table shows various plant products which exert anti-inflammatory potential through targeting various inflammation-related signaling molecules. Several phytochemicals and plant extract have been reported to modulate activities of TNF-α, ILs and IFN-γ. Additionally, they also inhibit the binding of spike protein (ACE2 receptor), cyclooxygenase-2, iNOS and CRP production. Thus, plant extracts and phytochemicals can achieve its anti-inflammatory effects against SARS-CoV-2.
Class Plant Product Effects Reference
Phenolics Curcumin Inhibits TNF-α, serum IL-6 and CRP production. [1][3]
Phenolics Chloroquine Inhibits IFN-γ, IL-1, IL-6 and TNF-α production. [4][5]
Phenolics Punicalagin Inhibits IL-6 and TNF-α production. [17][18]
Phenolics Ascorbic acid Inhibits IFN-γ, TNF-α and IL-6 production. [9][10]
Anthraquinone Emodin Inhibits binding of spike protein to ACE2 receptor. [13]
Flavanol EGCG Inhibits IL-6, TNF-α and IL-8 production. [14]
Phenolics Hydroxychloroquine Inhibits IL-1, IL-6 IFN-γ and TNF-α production. [6][7]
Flavone Luteolin Inhibits production of TNF-α-induced MCP-1, ICAM-1 and VCAM-1. [23]
Flavone Apigenin Inhibits TNF-α, IL-6, IL-8, and GM-CSF expression. [25][26]
Carotenoid Fucoxanthin Decreases TNF-α production. [9]
Phenolics Resveratrol Inhibits TNF-α, IL-8 and IL-6 and MCP-1 expression. [20]
Phenolics Gallic acid Inhibits IL-6 production. [17]
Phenolics Chebulagic acid (Triphala) Inhibits IL-6, IL-8 and MCP-1 expression. [19]
Phenolics Chebulinic acid (Triphala) Inhibits IL-6, IL-8 and MCP-1 expression. [19]
Flavonol Quercetin Inhibits IL-6, TNF-α and IL-1β production. [22]
Flavonol Fisetin Inhibits IL-6, TNF-α, MCP-1 and IL-8 production. [27]
Flavone Rutin Inhibits expression of NO and TNF-α. [28]
Flavonol Kaempferol Inhibits secretion of MCP-1. [30]
Phenolics Ellagic acid Inhibits IL-6 production. [17]
Flavonol Myricetin Inhibits IL-6, TNF-α, NO, and iNOS. [32]
Flavanone Hesperetin Inhibits IL-1β, IL-6 and TNF-α production. [33][34]
Flavanone Naringenin Inhibits IL-6 and TNF-α production. [35]
Glycoside Isorhamnetin Inhibits IL-6 production. [37]
Flavone Chrysin Inhibits IL-1β expression. [38]
Flavonol Galangin Inhibits IL-1β expression. [38]
Phenolics Theaflavin Inhibits expression of IL-6, MCP-1 and ICAM-1 [39]
Isoflavonoid Genistein Inhibits IL-6 and TNF-α production. [40]
Flavone Baicalein Inhibits production of IL-6, TNF-α, IL-1β and NO. [42]
Phenolics Ferulic acid Inhibits production TNF-α, IL-6 and IL-10 [43]
Flavonol Kaempferol7-o-β-d-glucoside Inhibits expression of TNF-α, IL-6, IL-1β, iNOS and COX-2. [31]

2. Antiviral Activities of Plant Products: An Insight into Molecular Mechanisms

Various antiviral plant products and their mechanisms of action have been suggested in this section. Several studies have shown the therapeutic potential of many plant products, which include flavonoids, alkaloids, terpenoids, chalcones, glycosides, phenolics, tannins, and lignins. There are many molecular targets that had been anticipated in view of finding a potent target that may lead to the development of a novel strategy for the prevention and treatment of coronaviruses. Various possible molecular targets were identified in order to treat and prevent the previously occurring SARS-CoV and MERS-CoV outbreaks through the identification and application of antiviral plant products. These molecular targets include spike glycoproteins S1 and S2 (domains), virus-encoded proteases such as 3C-like cysteine protease (3CL pro) and papain-like cysteine protease, and virus-encoded enzymes such as RNA-dependent RNA polymerase and NTPase/helicase. Herein, researchers repurposed several plant products to consider them as the possible hope to controlling the novel pandemic, as earlier many plant products such as chloroquine and hydroxychloroquine have proven their anti-malarial potential.
Hesperidin is commonly found in citrus fruits, and its aglycone metabolite is known as hesperetin. In a recent study, hesperetin and hesperedin were considered to determine whether they exhibit inhibitory activities against SARS-CoV-2. The results of the in-silico study showed that both compounds have the ability to bind with TMPRSS2 and ACE2, and they suppressed the infection of VeroE6 cells with SARS-CoV-2 by inhibiting the interaction between S protein and ACE2, which indicates that both compounds can be used for the treatment and prevention of SARS-CoV-2 [44]. Honokiol, the main compound found in Magnolia trees, has previously been shown to have anti-cancer and anti-inflammatory properties. In an interesting study, honokiol was shown to inhibit viral growth and proliferation in cell culture. Notably, honokiol protected VeroE6 cells from the SARS-CoV-2 infection with an EC50 value of 7.8 µM, decreasing the viral RNA copies and viral titers. Further investigations showed that honokiol inhibited SARS-CoV-2 replication, and they also suggested that honokiol is also active against many variants of SARS-CoV-2, including the Omicron variant and other human coronaviruses [45].
In a recent study, Allium sativum, Nigella sativa, Camellia sinensis, Curcuma longa, and Eucalyptus sp. were analyzed for phytochemicals, which revealed that naringenin and saikosaponins show promising anti-SARS-CoV-2 effects [46]. Another study investigated a library of plant products and identified myricetin and scutellarein as the novel inhibitors of the SARS-CoV helicase, nsP13 [47]. Quercetin and epigallocatechin gallate are some of the important flavonoids which played pivotal roles in improving the health status, as well as fighting against many pathogens. They were investigated for their antiviral potential due to antioxidant and anti-inflammation properties and were found to stop SARS-CoV replication via the amelioration of 3CLpro expressed in Pichia pastoris [48]. Ricinus communis, a medicinal plant, is known for its various pharmacological properties, including antioxidation, antibacterial, antiviral, and anti-inflammatory actions, which were studied to determine its anti-SARS-CoV-2 effects. The studies showed that Ricinus communis containsricinine and lupeol as their chief phytoconstituents, and a methylene chloride extract of this plant exerts prominent virucidal activity against SARS-CoV-2. However, they further showed that ricinine exhibited superior anti-SARS-CoV-2 effects with an IC50 value of 2.5 µg/mL, followed by lupeol with an IC50 value of 19.5 µg/mL [49].
In an in-silico study, luteolin was reported to bind with the spike glycoprotein, RdRp, and ADP phosphatase of non-structural protein-3, suggesting luteolin as an anti-SARS-CoV-2 compound [50]. Four flavonoids, amentoflavone, luteolin, apigenin, and quercetin, have been demonstrated to inhibit the SARS-CoV; however, amentoflavone and luteolin significantly inhibited 3CL proteinase (3CL pro) activity at lower doses, comparatively [51]. Another study screened several phytochemicals for their potential activities against 3CL pro and PL pro, and out of 32 phytocompounds, only amentoflavone and gallocatechin gallate were shown to possess the best binding with 3CL pro and PL pro, which may help in the development of amentoflavone and gallocatechin gallate as drug candidates against 3CL pro and PL pro as therapeutics for SARS-CoV-2 [52]. An aqueous extract of Houttuynia cordata was found to be enriched with flavonoids such as quercetin, quercitrin, and isoquercitrin, which demonstrated the inhibition of herpes simplex virus (HSV) and SARS-CoV [53]. Five Isatisindigotica root-extracted compounds and seven plant-derived compounds were evaluated for their anti-SARS-CoV activities, and in vitro studies suggested that hesperetin, sinigrin, and aloe emodin were observed as the most effective inhibitors of cleavage activity of the 3CL pro [54]. Another in silico study has screened 41 antiviral compounds from Indian medicinal plants, and among them, amentoflavone, hypericin, and torvoside H were suggested to serve as potential inhibitors against SARS-CoV-2 [55].
Glycyrrhizin, a compound mainly found in Glycyrrhiza glabra, exerts anti-inflammatory activities and has also been investigated for its anti-SARS-CoV effects. One of the research articles has indicated that glycyrrhizin may inhibit the replication of SARS-CoV at higher doses, which may cause toxicity to normal cells as well [56]. Another study demonstrated that glycyrrhizin and licorice extract possess multiple health benefits, including antioxidant, antibacterial, and anti-inflammatory activities. Furthermore, the researchers showed that glycyrrhizin and licorice extract exhibited significant inhibitory activity against SARS-CoV-2, which was due to the inhibition of viral entry through the inhibition of viral interaction with the cell membrane receptor ACE2 [57]. Cinanserin, a compound naturally available in Houttuynia cordata plant species, inhibited SARS-CoV replication, most likely through the inhibition of 3CL proteinase activity [58]. Lycorine, a compound extracted from the medicinal herb Lycoris radiata, demonstrated anti-SARS-CoV activities [59]. The same research article has explored many medicinal herbs for their effectiveness against the SARS-CoV and reported that out of several, only four Chinese medicinal plants, including Artemisia annua L. (ethanolic extract), Lycoris radiata (ethanolic extract), Pyrrosia lingua (chloroform extract), and Lindera aggregate (sims) kasterm (ethanolic extract) inhibited the activity of the SARS-CoV [59]. Emodin, a compound specifically extracted from the genera Rheum and Polygonum, was found to impede the growth of SARS-CoV through the inhibition of spike proteins and ACE2 interaction [13]. Aqueous extracts of Rheum officinale Baill and Polygonum multiflorum Thunb (Chinese medicinal herbs) significantly inhibited the host–pathogen interaction through the inhibition of spike proteins and ACE2 interactions [13].
Zingiber officinale, Scutellariabaicalensis, Nigella sativa, Allium sativum, Camellia sinensis, Hypericum perforatum, and Glycyrrhiza glabra were studied to identify phytochemicals and their anti-SARS-CoV-2 activities. The results of the study showed that they possess different types of terpenoids, out of which emodin and baicalin inhibited S protein, iguesterin inhibited 3CL pro, cryptotanshinone targeted PL pro and sotetsuflavone inhibited RdRp, thus they exhibited potent anti-SARS-CoV-2 activities [60]. Houttuynia cordata Thunb, a member of the Saururaceae family, was screened to check whether the plant displays anti-SARS-CoV activities. As a result, an aqueous extract of this plant inhibited both 3CL pro and RdRp of SARS-CoV [61]. In order to identify the potential inhibitory effects against SARS-CoV, more than 200 Chinese medicinal herbs were screened, but only a few of them showed antiviral activities. Gentiana scabra, Dioscorea batatas, Cassia tora, Taxillus chinensis, and Cibotium barometz inhibited Vero E6 cell proliferation and viral replication; however, Cibotium barometz and Dioscorea batatas were found to be significant inhibitors of 3CL pro [62]. Rheum palmatum, a Chinese medicinal herb, was also investigated and was found to prevent the replication of SARS-CoV by inhibiting 3CL pro [63]. Toona sinensis Roem, a plant species in the Meliaceae family, was studied for antiviral effects, and the results showed that the plant inhibited SARS-CoV replication in a promising way [64]. Prunella vulgaris and Saussurea lappa were studied among 121 Chinese herbs, and the two compounds tetra-o-galloyl-D-glucose and luteolin extracted from these plants demonstrated antiviral potential by inhibiting spike protein S2 and preventing SARS-CoV entry into Vero E6 cells [65]. Anthemis hyaline, Nigella sativa, and Citrus sinensis extracts have been proven to inhibit the replication of the coronavirus, but the molecular mechanism of the inhibiting replication machinery was not clearly understood [66]. Moreover, recently, two important phytochemicals, curcumin and catechin, were studied for their inhibitory activities against SARS-CoV-2. The results of the in-silico study revealed a high potential to bind with S protein and ACE2, implying that both polyphenolic compounds could be used as anti-SARS-CoV-2 agents [67]. In addition to immunomodulatory, antioxidant, and anti-inflammatory actions, oxidized EGCG also displayed inhibitory activity against SARS-CoV-2 [68]. Furthermore, the flavonoids EGCG and theaflavin were shown to block the virus particle from attaching to the ACE2 and glucose-regulated protein (GRP) 78 receptors. In particular, an in-silico approach revealed that EGCG binds to 3CL pro and both possessed anti-inflammatory properties to control the actions of inflammatory cytokines. All of these experimental results suggest that both flavonoids could be used in the treatment and prevention of SARS-CoV-2 [69]. The impact of bioactive metabolites derived from medicinal plants on molecular targets of various steps of the multiplication process of SARS-CoV-2 has been presented in Figure 2.
Molecules 28 00795 g002 550
Figure 2. Major molecular targets of phytochemicals in combating SARS-CoV-2. Phytochemicals and plant extracts can target angiotensin-converting enzyme (ACE-2), RNA dependent RNA polymerase (RdRp), Papain-like protease (PL pro) and 3-chymotrypsin-like cysteine protease (3CL pro). The illustration was created at BioRender.com (an online available tool for illustrations).
Recently, an in-silico study revealed that flavonoids such as apigenin, quercetin, and kaempferol bind with the spike receptor protein of SARS-CoV-2; however, quercetin was found to be the most active phytochemical against SARS-CoV-2 and could be a better inhibitor in combating SARS-CoV-2 infections [70]. In silico and in vitro studies suggested that out of many studied phytochemicals, curcumin, EGCG, theaflavin and resveratrol were found to be effective in impeding the coronavirus [71]. Resveratrol, a polyphenolic compound, has been investigated for its antiviral activities against SARS-CoV-2. The results of the study showed that this compound exhibited anti-inflammatory potential and inhibited SARS-CoV-2 replication in human primary bronchial epithelial cell cultures. The low bioavailability (oral administration) of this compound limits its use in clinical practices; however, a topical administration through inhaled formulations may provide a sufficient amount of resveratrol in the lung airways (the site for the entry of SARS-CoV-2) [72]. In an interesting study, black garlic and 49 polyphenolic compounds were screened for their anti-SARS-CoV-2 activities. The results of the study showed that the black garlic extract exerted its inhibitory effect on purified main protease enzyme (Mpro) with an IC50 value of 137 μg/mL, whereas the mixture of tannic acid, daidzein, and puerarin and/or myricetin was found to enhance the inhibitory effects on Mpro [73]. A recent study found that naringenin can be a promising novel pharmacological compound with safe and efficient therapy for SARS-CoV-2 infections, as naringenin strongly inhibited SARS-CoV-2 replication in VeroE6 cells through targeting endo-lysosomal two-pore channels [74].
Some of the biflavonoids and diterpenoids extracted from a traditionally used medicinal plant, Torreya nucifera, were predicted to inhibit the 3CL pro of SARS-CoV. The diterpenoids, ferruginol, o-acetyl-18-hydroxyferruginol, kayadiol and 18-oxoferruginol also demonstrated inhibitory potential against 3CL pro activity of SAS-CoV, slightly more than other isolated diterpenoids such as methyl dehydroabietate, 18-hydroxyferruginol, and hinokiol andisopimaric acid [51]. The geranylated flavonoids extracted from Paulownia tomentosa were found capable of targeting the SARS-CoV papain-like protease (PL pro) in which the compounds tomentin E, tomentin B, and tomentin A were demonstrated as potent inhibitors more comparatively than tomentin C and tomentin D [75]. Many polyphenolic compounds were isolated from the plant species Broussonetia papyrifera for the evaluation of anti-PL pro and anti-3CL pro activities in coronaviruses. Among all of the evaluated compounds, papyriflavonol A, broussochalcone A, broussochalcone B, and kazinol J inhibited SARS-CoV-PL pro more effectively in contrast to other polyphenols including 4-hydroxyisolonchocarpin, 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane, kazinol A, kazinol B, broussoflavan A, and kazinol F. However, all the polyphenols were also effective against SARS-CoV 3-chymotripsin-like protease [76]. The ethanolic seed extracts from the medicinal plant Psoralea corylifolia had earlier demonstrated the significant anti-SARS-CoV PL pro potential. The purification process identified many aromatic compounds such as bavachinin, neobavaisoflavone, isobavachalcone, 4′-O-methylbavachalcone, psoralidin and corylifol A, and was reported to be endowed with good PL pro activities. Both the aromatic compounds psoralidin and isobavachalcone displayed potent efficacies in deterioration of the virus replication [77]. Anti-SARS-CoV plant products also comprise of tylophorine compounds purified from Tylophora indica that inhibit the SARS-CoV papain-like protease to curb the viral load via targeting virus replication [78].
With an extending approach in view of repurposing the plant products, Salvia miltiorrhiza-derived tanshinones have been reported as inhibiting the coronaviral cysteine proteases. The plant derived tanshinones include tanshinone IIA, tanshinone IIB, methyl tanshinonate, cryptotanshinone, tanshinone I, dihydrotanshinone I, and rosmariquinone. Dihydrotanshinone I, rosmariquinone, and tanshinone IIB suppressed the viral replication by inhibiting the 3CL pro while cryptotanshinone, tanshinone IIA, and dihydrotanshinone I inhibited 3PL pro activity specifically [79]. Anti-SARS-CoV effects of many medicinal herbs including Cinnamomi cortex (Cinnamomum verum), Forsythiae Fructus (Forsythia suspensa), Scutellariae Radix (Scutellaria baicalensis), Astragali Radix (Astragalus propinquus), Bupleuri Radix (Bupleurum chinensis) and Glycyrrhizae Radix (Glycyrrhiza uralensis) were also envisaged and only a purified compound, procyanidin, and a Cinnamomum verum extract were found to be significantly effective in decreasing coronaviral load while the molecular mechanism was not clearly understood [80]. In an in vitro study, plant-synthesized terpenoids and lignoids were investigated against SARS-CoV replication and proliferation in VeroE6 cells in addition to SARS-CoV 3CL pro. Of the hundreds of plants tested for derived compounds, only ferruginol, 8β-hydroxyabieta-9(11),13-dien-12-one, 7β-hydroxydeoxycryptojaponol, 3β-12-diacetoxyabieta-6,8,11,13-tetraene, betulonic acid, and savinin were found to promote exacerbation of SARS-CoV replication [81].

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Shoaib Shoaib
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Mohammad Azam Ansari
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Geetha Kandasamy
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Rajalakshimi Vasudevan
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Umme Hani
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Waseem Chauhan
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Maryam S. Alhumaidi
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Khadijah A. Altammar
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Sarfuddin Azmi
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Wasim Ahmad
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Shadma Wahab
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Najmul Islam
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Update Date: 02 Feb 2023
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